GSK-3 is a serine/threonine kinase, for which two isoforms, α and β, have been identified and found to be coded for by separate genes (see non-patent document 1). Both of the GSK-3 isoforms adopt a monomer structure and are homeostatically activated in resting cells. GSK-3 was first identified as a kinase which inhibits activity of glycogen synthases by direct phosphorylation (see non-patent document 2). It is thought that stimulation by insulin leads to inactivation of GSK-3, thereby permitting activation of glycogen synthases and also eliciting insulin functions such as glucose transport. GSX-3 is further known to be inactivated by growth factors such as IGF-1 and FGF, via signals from receptor tyrosine kinases (see non-patent documents 3, 4, 5).
GSK-3 inhibitors are useful in the treatment of various diseases associated with GSK-3 activation. In addition, since GSK-3 inhibitors mimic activation of growth factor signaling pathways, they are also of use in treatment of diseases associated with inactivation of these signaling pathways. Several diseases for which GSK-3 inhibitors are believed to be effective are described below.
Type I diabetes is caused by autoimmune destruction of the β cells, or insulin-producing cells, of the pancreas, leading to insulin deficiency. Type I diabetes patients therefore require daily insulin injections for life support. Current insulin therapy, however, has not been successful in achieving the strict control of glucose levels accomplished by normal β cells. Type I diabetes therefore often leads to diabetes complications such as retinopathy, nephropathy, neuropathy and large artery impairment.
Type II diabetes is a multifactorial disorder wherein hyperglycemia is produced due to insulin resistance in the liver, skeletal muscle and fatty tissue, as well as insufficient secretion of insulin by the pancreas. This condition also results in numerous diabetes complications such as retinopathy, nephropathy, neuropathy and large artery impairment. Skeletal muscle is the major tissue involved in insulin-mediated glucose uptake, and the glucose taken up into the cells is either, metabolized through the glycolytic pathway/TCA cycle or stored as glycogen. Glycogen storage in the skeletal muscle is an extremely important function for glucose homeostasis, but in type II diabetes patients the glycogen storage volume in skeletal muscle is reduced. GSK-3 acts to inhibit glycogen storage in peripheral tissue by phosphorylating glycogen synthase, and to lower insulin reactivity, leading to increased blood glucose levels.
According to a recent report, accelerated expression of GSK-3 is seen in the skeletal muscle of type II diabetes patients and an inverse correlation has been found between skeletal muscle GSK-3α activity and insulin function (see non-patent document 6). Also, overexpression of GSK-3β and active GSK-3β mutants (S9A, S9E) in HEK-293 cells suppresses glycogen synthase activity (see non-patent document 7). Reduction in insulin function has been observed when GSK-3β is overexpressed in CHO cells expressing insulin receptor and insulin receptor substrate 1 (IRS-1) (see non-patent document 8). A recent study using C57BL/6J mice prone to obese diabetes has demonstrated a connection between accelerated GSK-3 activity and progression of insulin resistance/type II diabetes (see non-patent document 9).
Lithium salts are already known as inhibitors of GSK-3 activity (see non-patent document 10). Treatment using lithium salts is reported to lower glucose levels in both type I and type II diabetes patients and to generally improve their condition (see non-patent document 11). However, lithium salts have also been reported to exhibit various effects on molecular targets other than GSK-3.
In consideration of the above, it is expected that GSK-3 inhibitors can serve as effective drug agents for amelioration of impaired glucose tolerance, type I diabetes, type II diabetes, and their related complications.
A link has also been suggested between GSK-3 and progression of Alzheimer's disease. Alzheimer's disease is characterized by formation of senile plaques in the brain from amyloid β peptide deposits, and subsequent formation of neurofibrillary changes. These neurofibrillary changes result in the deaths of large numbers of neurons, and lead to the symptom of dementia. GSK-3 is believed to contribute to abnormal phosphorylation-of Tau protein, which is connected with neurofibrillary changes, during the course of the disease (see non-patent document 12). It has also been reported that GSK-3 inhibitors prevent neuronal death (see non-patent document 13). These findings suggest that application of GSK-3 inhibitors for Alzheimer's disease may slow progression of the condition. While treatment methods currently exist which employ agents for symptomatic therapy of Alzheimer's disease (see non-patent document 14), no agents are known that prevent neuronal death and slow progression of the condition. It is therefore expected that GSK-3 inhibitors can serve as effective drug agents for amelioration of Alzheimer's dementia.
GSK-3 inhibitors have been reported to suppress neuronal death, and especially neuronal death due to glutamate-mediated hyperexcitation (see non-patent documents 15 and 16). This suggests the possibility that GSK-3 inhibitors may be useful for treatment of bipolar affective disorder (manic depression), epilepsy and a host of neurodegenerative disorders and neural diseases. As neurodegenerative disorders there may be mentioned Alzheimer's disease described above, as well as AIDS encephalopathy, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, disseminated sclerosis, Pick's disease, progressive supranuclear palsy, and the like. Glutamate-mediated hyperexcitation is believed to be a cause of brain disorders in such conditions as cerebral apoplexy (cerebral infarction, encephalorrhagia, subarachnoid hemorrhage), traumatic encephalopathy/spinal injury, bacterial/viral infection and the like, and GSK-3 inhibitors are therefore expected to be useful against these conditions as well. All of these disorders are accompanied by death of neurons, and at the current time no drug exists that can effectively suppress such neuronal death. It is therefore believed that GSK-3 inhibitors can serve as effective drug agents for amelioration of various forms of neurodegenerative disorders, bipolar affective disorder (manic depression), epilepsy, cerebral apoplexy, traumatic encephalopathy/spinal injury, and the like.
In vitro research has also been reported indicating that Wint10B strongly suppresses differentiation of preadipocytes to mature adipocytes (see non-patent document 17). GSK-3 specific inhibitors mimic the Wint10B signal in adipose cells, and particularly stabilize free cytosolic β-catenin to block induction of c/EBPα and PPARγ, thereby inhibiting adipogenesis (see non-patent document 18). These findings have led to expectations for GSK-3 inhibitors as effective agents for treatment of obesity.
β-Catenin is known as a biological substrate of GSK-3. β-Catenin is phosphorylated by GSK-3 and undergoes proteosome-dependent degradation (see non-patent document 19). Since transient β-catenin stabilization is thought to play a role in hair development (see non-patent document 20), this suggests that GSK-3 inhibitors may serve as effective drug agents for alopecia.
In addition, research on fibroblasts from GSK-3β knockout mice has raised the possibility that GSK-3β upregulates activity of transcription factor NFκ-B. (see non-patent document 21). NFκ-B is responsible for cell response to a large number of inflammatory stimuli. It is therefore believed that GSK-3 inhibitors may, through downregulation of NFκ-B activity, serve as effective drug agents for treatment of inflammatory conditions such as deformant arthritis, rheumatism, atopic dermatitis, psoriasis, ulcerative colitis, Crohn's disease, sepsis, generalized inflammatory reaction syndrome, and the like.
The transcription factor NF-AT is dephosphorylated by calcineurin, resulting in a reinforced immune response (see non-patent document 22). GSK-3 instead phosphorylates NF-AT and exports it out of the nucleus, thereby working in a direction to suppress expression of early immune response genes. These findings suggest that GSK-3 inhibitors may serve as effective drug agents promoting immune activation for cancer immunotherapy and the like.
As substances previously known to have GSK-3 inhibiting activity there have been reported hymenialdisine derivatives (see non-patent document 23 and patent document 1), maleinimide derivatives (see non-patent document 24), Paullone derivatives (see non-patent document 25 and patent document 2), purine derivatives (see patent document 3), pyrimidine and pyridine derivatives (see patent document 4), hydroxyflavone derivatives (see patent document 5), pyrimidone derivatives (see patent documents 6, 7, 8, 9, 10, 11, 12 and 13), pyrrole-2,5-dione derivatives (see patent documents 14 and 15), diamino-1,2,4-triazolecarboxylic acid derivatives (see patent document 16), pyrazine derivatives (see patent document 17), bicyclic inhibitors (see patent document 18), indirubin derivatives (see patent document 19), carboxamide derivatives (see patent document 20), peptide inhibitors (see patent document 21), 2,4-diaminothiazole derivatives (see patent document 22), thiadiazolidinedione derivatives (see patent document 23) and aromatic amide derivatives (see patent document 24).    Non-patent document 1: Trends Biochem. Sci., 1991, Vol. 16, p. 177.    Non-patent document 2: Eur. J. Biochem., 1980, Vol. 107, p. 519.    Non-patent document 3: Biochem. J. (UK), 1993, Vol. 294, p. 625.    Non-patent document 4: Biochem. J. (UK), 1994, Vol. 303, p. 21.    Non-patent document 5: Biochem. J. (UK), 1994, Vol. 303, p. 27.    Non-patent document 6: Diabetes USA, 2000, Vol. 49, p. 263.    Non-patent document 7: Proc. Natl. Acad. Sci. USA, 1996, Vol. 93, p. 10228.    Non-patent document 8: Proc. Natl. Acad. Sci. USA, 1997, Vol. 94, p. 9660.    Non-patent document 9: Diabetes USA, 1999, Vol. 48, p. 1662.    Non-patent document 10: Proc. Natl. Acad. Sci. USA, 1996, Vol. 93, p. 8455.    Non-patent document 11: Biol. Trace Elements Res., 1997, Vol. 60, p. 131.    Non-patent document 12: Acta Neuropathol., 2002, Vol. 103, p. 91.    Non-patent document 13: J. Neurochem., 2001, Vol. 77, p. 94.    Non-patent document 14: Expert Opin. Pharmacother., 1999, Vol. 1, p. 121.    Non-patent document 15: Proc. Natl. Acad. Sci. USA, 1998, Vol. 95, p. 2642.    Non-patent document 16: J. Neurochem., 2001, Vol. 77, p. 94.    Non-patent document 17: Science, 2000, Vol. 289, p. 950.    Non-patent document 18: J. Biol. Chem, 2002, Vol. 277, p. 30998.    Non-patent document 19: EMBO J., 1998, Vol. 17, p. 1371.    Non-patent document 20: Cell, 1998, Vol. 95, p. 605.    Non-patent document 21: Nature, 2000, Vol. 406, p. 86.    Non-patent document 22: Science, 1997, Vol. 275, p. 1930.    Non-patent-document 23: Chemistry & Biology, 2000, Vol. 7, p. 51.    Non-patent document 24: Chemistry & Biology, 2000, Vol. 7, p. 793.    Non-patent document 25: Eur. J. Biochem., 2000, Vol. 267, p. 5983.    Patent document 1: WO01/41768 pamphlet    Patent document 2: WO01/60374 pamphlet    Patent document 3: WO98/16528 pamphlet    Patent document 4: WO99/65897 pamphlet    Patent document 5: WO00/17184 pamphlet    Patent document 6: WO00/18758 pamphlet    Patent document 7: WO01/70683 pamphlet    Patent document 8: WO01/70729 pamphlet    Patent document 9: WO01/70728 pamphlet    Patent document 10: WO01/70727 pamphlet    Patent document 11: WO01/70727 pamphlet    Patent document 12: WO01/70726 pamphlet    Patent document. 13: WO01/70725 pamphlet    Patent document 14: WO00/21927 pamphlet    Patent document 15: WO01/74771 pamphlet    Patent document 16: WO01/09106 pamphlet    Patent document 17: WO01/44206 pamphlet    Patent document 18: WO01/44246 pamphlet    Patent document 19: WO01/37819 pamphlet    Patent document 20: WO01/42224 pamphlet    Patent document 21: WO01/49709 pamphlet    Patent document 22: WO01/56567 pamphlet    Patent document 23: WO01/85685 pamphlet    Patent document 24: WO01/81345 pamphlet
It is an object of the present invention to provide clinically useful novel compounds with selective and powerful inhibiting action against GSK-3.